Bacterial interference creates an ecological competition between commensal bacteria and pathogenic species. Like microbial competition via fermentation in a ripening fruit, bacterial interference via fermentation has been found in the deep-seated skin abscesses where is an anaerobic microenvironment, allowing bacteria to ferment carbohydrates to short-chain fatty acids (SCFA). Fermentation of milk with gut- friendly bacteria, yogurt is an excellent aid to balance the bacteriological ecosystem in the human intestine. Previous studies indicated that SCFAs in skin played a curial role in influencing the predominant residence of bacteria on normal human skin. Thus, we hypothesize that fermentation products of human skin commensal bacteria, like yogurt made by fermentation with friendly gut bacteria, can function as skin probiotics for treatment of skin infections by pathogens. In this proposal, we will use the bacterial fermentation in skin microbiome as probiotics (Bfismp) against methicillin-resistant Staphylococcus aureus (MRSA). It remains as an unmet challenge to develop effective therapeutics for MRSA treatment because of its formidable resistance against multiple traditional antibiotics. Everyone carried Propionibacterium acnes (P. acnes), a Gram-positive and skin commensal bacterium accounting for more than 50% of the total skin microbiome. P. acnes was named for its ability to ferment carbohydrates to propionic acid. Our preliminary results have demonstrated that propionic acid effectively suppressed the growth of USA300, a community-acquired MRSA, both in vitro and in vivo. More intriguingly, we also demonstrated that fermented media (acted as Bfismp) of P. acnes exerted an inhibitory effect on the growth of USA300. Three Specific Aims we proposed are to 1) Use the Bfismp against S. aureus/MRSA infection, establish the profiles of SCFA in Bfismp, and examine the anti-S. aureus/MRSA activity of Bfismp in vitro; 2) Explore the action mechanism of Bfismp on decreasing the intracellular pH of S. aureus/MRSA, and validate the in vivo potency of Bfismp in inhibiting skin infection of S. aureus/MRSA; and 3) Determine the response of skin cells to Bfismp, and test the possible side effects caused by topical application of Bfismp. The STTR Phase I project will be conducted based on collaboration between University of California, San Diego and Surface Bioadvances Inc., a San Diego company with a business aim to develop therapeutics against infectious diseases. We have formed a solid research team consisting of a skin bacteriologist (Dr. Huang; PI at UCSD), a molecular biologist (Dr. Jiang at Surface Bioadvances Inc.), a dermatologist (Dr. Gallo), and microbiologist (Dr. Nizet). When successful, bactericides derived from fermentation of skin commensal bacteria will benefit the entire community of patients with MRSA infections consisting of over 126,000 patients per year in United States. The impact of this proposal includes opening a novel skin-care industry of using Bfismp for treating skin infection and/or promoting skin health.